Process methods for phosphatidylinositol 3-kinase inhibitors

ABSTRACT

A process for the synthesis of quinazolinone containing compounds which may be useful for the treatment of cancer, is hereby disclosed. In addition, compound intermediates relating to these processes are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/817,044, filed Nov. 17, 2017, which is a divisional of U.S.patent application Ser. No. 15/392,198, filed Dec. 28, 2016, which is adivisional of U.S. patent application Ser. No. 14/575,670, filed Dec.18, 2014, now U.S. Pat. No. 9,567,337, issued Feb. 14, 2017, whichclaims the benefit of and priority to U.S. Provisional Application Ser.No. 61/919,548, filed Dec. 20, 2013, the disclosures of which are herebyincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The present disclosure relates generally to the synthesis or preparationof certain phosphatidylinositol 3-kinase (PI3K) inhibitors and theirsynthetic intermediates. Inhibitors of PI3K, such as quinazoline-purinylcontaining compounds, may be useful in treating PI3K-mediated disorderssuch as cancer. There is a need to have alternative processes in makingsuch PI3K inhibitors.

BRIEF SUMMARY OF THE INVENTION

The present disclosure provides a process of making certain PI3Kinhibitors and compound intermediates thereof.

In one embodiment, the application discloses processes for synthesizinga compound of formula I:

or a salt thereof.

In another embodiment, the application discloses processes forsynthesizing a compound of formula II:

or a salt thereof.

In an alternative embodiment, the application discloses processes forsynthesizing a compound of formula III:

or a salt thereof.

In one embodiment, the application discloses a process for synthesizinga compound of formula 1:

or a salt thereof, comprising step a) combining a compound of formula 2:

or a salt thereof,

and a compound of formula 3:

wherein the compound of formula 1 or a salt thereof is synthesized,wherein R¹ is halo; R² is selected from the group consisting of H andoptionally substituted C₁-C₈ alkyl; and R³ and R⁴ are each independentlyselected from the group consisting of hydrogen, an amino protectivegroup and an optionally substituted purinyl group.

In a further embodiment the process further comprises step b) combiningthe compound of formula 1 or a salt thereof; and

a compound of formula 22:

wherein n is 0-5; and each R⁵ is independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

wherein a compound of formula 4:

or a salt thereof is synthesized.

In yet a further embodiment, the process further comprises step c)combining the compound of formula 4 or a salt thereof, wherein at leastone of R₃ and R₄ of the compound of formula 4 is an amino protectivegroup; and one or more reagents, wherein the one or more reagents areused to remove the amino protective group; wherein a compound of formula5:

or a salt thereof is synthesized;

step d) combining the compound of formula 5 or a salt thereof and acompound of formula 6:

wherein X is selected from the group consisting of halogen, mesyl,mesylate, tosyl and tosylate; and R⁶ is hydrogen or an amino protectivegroup; wherein a compound of formula 7:

or a salt thereof is synthesized; and if R⁶ is an amino protectivegroup, step e) further combining the compound of formula 7 or a saltthereof; and one or more reagents, wherein the one or more reagents areused to remove the amino protective group, wherein a compound of formulaI:

or a salt thereof is synthesized.

In one embodiment, the present application discloses a process forsynthesizing a compound of formula 8:

or a salt thereof, comprising step a) combining a compound of formula 9

or a salt thereof, and a compound of formula 10

wherein the compound of formula 8 or a salt thereof is synthesized.

In a further embodiment, the process further comprises step b) combiningthe compound of formula 8 or a salt thereof and aniline, wherein acompound of formula 11:

or a salt thereof is synthesized.

In yet a further embodiment, the process further comprises step c)combining the compound of formula 11 or a salt thereof and an acid,wherein a compound of formula 12:

or a salt thereof is synthesized; step d) combining the compound offormula 12 or a salt thereof and a compound of formula 13

wherein a compound of formula 14:

or a salt thereof is synthesized; and

step e) combining the compound of formula 14 or a salt thereof and anacid, wherein a compound of formula II:

or a salt thereof is synthesized.

In an alternative embodiment, the application discloses a process forsynthesizing a compound of formula 15:

or a salt thereof, comprising step a) combining a compound of formula16:

or a salt thereof,

and a compound of formula 10a:

wherein the compound of formula 15 or a salt thereof is synthesized.

In a further embodiment, the process farther comprises step b) combiningthe compound of formula 15 or a salt thereof and aniline, wherein acompound of formula 17:

or a salt thereof is synthesized.

In yet a further embodiment, the process further comprises step c)combining the compound of formula 17 or a salt and an acid thereof,wherein a compound of formula 18:

or a salt thereof is synthesized;

step d) combining the compound of formula 18 or a salt thereof and acompound of formula 13

wherein a compound of formula (19):

or a salt thereof is synthesized; and

step e) combining the compound of formula 19 or a salt thereof and anacid, wherein the compound of formula III:

or a salt thereof is synthesized.

In some embodiments, the application discloses the intermediatecompounds formed from the processes disclosed herein. In someembodiments, the application discloses compounds selected from the groupconsisting of

and salts thereof. In certain embodiments, compounds of formula (8),(15), (14), (19), (20), and (21), are disclosed. In certain embodiments,pharmaceutically acceptable salts of the compounds of formula (8), (15),(14), (19), (20), and (21), are disclosed.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “about” includes and describes the value or parameter per se.For example, “about x” includes and describes “x” per se. In certainembodiment, the term “about” when used in association with ameasurement, or used to modify a value, a unit, a constant, or a rangeof values, refers to variations of +/−1-10%. In some embodiments, theterm “about” when used in association with a measurement, or used tomodify a value, a unit, a constant, or a range of values, refers tovariations of +/−5%. In some embodiments, the term “about” when used inassociation with a measurement, or used to modify a value, a unit, aconstant, or a range of values, refers to variations of +/−10%.

The term “between” includes and describes the value or parameter per se.For example, “between x and y” includes and describes “x” and “y” perse.

The term “and/or” includes subject matter in the alternative as well assubject matter in combination. For instance, “x, and/or y”, includes “xor y” and “x and y”.

The term “alkyl” as used herein refers to a straight or branched chain,saturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C₁-C₈)alkyl is meant to include, but is not limited to methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, to butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein throughout.

The term “substituted alkyl” refers to: 1) an alkyl group as definedabove, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2or 3 substituents) selected from the group consisting of alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, nitro, thiol, cyano, cycloalkyl,heterocyclyl, aryl, and heteroaryl.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This teen is exemplified by groups such as methylene (−CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “substituted alkylene” refers to an alkylene group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group —O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂₎, and the like.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃₎, and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “hydroxy” or “hydroxyl” refers to a group —OH.

The term “alkoxy” refers to the group R—O—, where R is alkyl; andincludes, by way of example, methoxy, ethoxy n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy,1,2-dimethylbutoxy, and the like.

The term “substituted alkoxy” refers to the group R—O—, where R issubstituted alkyl, where substituted alkyl, substituted alkenyl andsubstituted alkynyl are as defined herein.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl andthe like or multiple ring structures such as adamantanyl andbicyclo[2.2.1]heptanyl or cyclic alkyl groups to which is fused an arylgroup, for example indanyl, and the like, provided that the point ofattachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,nitro, thiol, cyano cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings naphthyl, fluorenyland anthryl). In some embodiments, aryls include phenyl, fluorenyl,naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3substituents), selected fromthe group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “substituted purinyl” refers to a purinyl having 1, 2, 3, 4, or5 substituents (in some embodiments 1, 2, or 3 substituents), eachindependently selected from the group consisting of alkyl alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, nitro, thiol, cyano, cycloalkyl,heterocyclyl, aryl, and heteroaryl. In some embodiments, purinyl issubstituted with 1, 2, or 3 substituents selected from the groupconsisting of methyl, ethyl, propyl, NH₂, and N(CH₃)₂.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms, and from 1 to 10 heteroatoms or1 to 4 heteroatoms within the ring, each heteroatom independentlyselected from the group consisting of nitrogen, sulfur, phosphorus, andoxygen.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl,and heteroaryl. Examples of heterocyclics include tetrahydrofuranyl,morpholino, piperidinyl, and the like.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic, to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine. The term “partiallysaturated heteroaryl” refers to a heteroaryl having a structureequivalent to an underlying aromatic heteroaryl which has had one ormore double bonds in an aromatic ring of the underlying aromaticheteroaryl saturated. Examples of partially saturated heteroarylsinclude dihydropyrrole, dihydropyridine, 2-oxo-1,2-dihydropyridin-4-yl,and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such, heteroaryl groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents)selected from the group consisting alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl,and heteroaryl. Such heteroaryl groups can have a single ring (e.g.,pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl,benzothiazole or benzothienyl). Examples of nitrogen heterocyclyls andheteroaryls include, but are not limited to pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazolines,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, and the like as well asN-alkoxy nitrogen containing heteroaryl compounds.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen. Unless otherwise constrained by the definition,substituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl,aryl, and heteroaryl.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl,and heteroaryl.

The term “thiol” refers to the group —SH.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, an “alkyl-substitutedphenyl”, where the attachment sites are not explicit, may have anyavailable site of the alkyl group attached to any available site of thephenyl group. In this regard, an “available site” is a site of the groupat which a hydrogen of the group may be replaced with a substituent.

A compound of a given formula is intended to encompass the compounds ofthe disclosure, and the salts, esters, isomers, tautomers, solvates,isotopes, hydrates, and prodrugs of such compounds. Additionally, thecompounds of the disclosure may possess one or more asymmetric centers,and can be produced as a racemic mixture or as individual enantiomers ordiastereoisomers. The number of stereoisomers present in any givencompound of a given formula depends upon the number of asymmetriccenters present (there are 2^(n) stereoisomers possible where n is thenumber of asymmetric centers). The individual stereoisomers (includingindividual enantiomers and diastereoisomers) as well as racemic andnon-racemic mixtures of stereoisomers are encompassed within the scopeof the present disclosure, all of which are intended to be depicted bythe structures of this specification unless otherwise specificallyindicated. Compounds of the present disclosure include separablerotational isomers, or atropisomers.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term“(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Calm IngoldPrelog R S system. When the compound is a pure enantiomer, thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

“Tautomers” are structural isomers resulting from the migration of anatom or a functional group within the same organic molecule and lead toa change in one or more of its structural skeleton, electronic densitydistribution, and chemical properties. It is understood that compoundsdisclosed herein includes tautomeric forms although not necessarilyexplicitly shown. In one example, purine may be represented by any ofthe following tautomers:

Accordingly, a reference to any one of the purine tautomers includes theother tautomeric forms.

The term “amino protective group” is well understood by the personskilled in synthetic organic chemistry as a moiety that can beselectively installed onto and removed from a suitable amine functionalgroup. Amino protective groups, and methods for using them, aredescribed in the authoritative treatise on the subject, P. G. M. Wutsand T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4thEdition (Wiley, 2006). In some embodiments, the amino protective groupis selected from the group consisting of a carbamate, an amide, and asulfonamide. In some embodiments, the amino protective group is a benzylgroup, or a Schiff base.

Non-limiting examples of carbamate based amino protective groups includemethyl carbamate, 9-fluoroenylmethyl carbamate (FMOC),2,2,2-trichloroethyl carbamate, 2-trimethylsilylethyl carbamate,1,1-dimethylpropynyl carbamate, 1-methyl-1-phenethylc carbamate,1-methyl-1-(4-biphenylyl)ethyl carbamate, 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2-cyanoethyl carbamate, t-butyl carbamate,cyclobutyl carbamate, 1-methylcyclobutyl carbamate; 1-adamantylcarbamate, vinyl carbamate, allyl carbamate, cinnamyl carbamate,8-quinolyl carbamate, N-hydroxypiperidinyl carbamate,4,5-diphenyl-3-oxazolin-2-one, benzyl carbamate, p-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, 2,4-dichlorobenzylcarbamate, 5-benzisoxazolylmethyl carbamate, 9-anthrylmethyl carbamate,diphenylmethyl carbamate, isonicotinyl carbamate, and S-benzylcarbamate, N—(N′-phenylaminothiocarbonyl) derivative. In one embodiment,the amino protective group is selected from the group consisting methylcarbamate, t-butyl carbamate, vinyl carbamate, and allyl carbamate. Inanother embodiment, the amino protective group is selected from thegroup consisting of t-butyl carbamate (BOC) and 9-fluoroenylmethylcarbamate (FMOC).

Non-limiting examples of amide based amino protective groups includeN-formyl, N-acetyl, N-chloracetyl, N-trichloroacetyl, N-trifluoroacetyl,N-o-nitrophenylacetyl, N-o-nitrophoxyacetyl, N-acetoacetyl,N-3-phenylpropionyl, N-3-(p-hydroxyphenyl)propionyl,N-2-methyl-2-(o-nitrophenoxy)propionyl, N-4-chorobutyryl,N-o-nitrocinnamoyl, acetylmethionyl), N-benzoyl, N-phthaloyl, andN-dithiasuccinoyl. In one embodiment, the amino protective group isselected from the group consisting of N-formyl, N-acetyl, N-chloracetyl,N-trichloroacetyl, N-trifluoroacetyl, and N-acetoacetyl.

Other non-limiting examples of amino protective groups include N-allyl,N-phenacyl, N-3-acetoxypropyl, quaternary ammonium salts,N-methyoxymethyl, N-benzyloxymethyl, N-pivaloyloxymethyl,N-tetrahydropyranyl, N-2,4-dinitrophenyl, N-benzyl, N-o-nitrobenzyl,N-di(p-methoxyphenyl)methyl, N-triphenylmethyl,N-(p-methyoxyphenyl)diphenylmethyl, N-diphenyl-4-pyridylmethyl,N-2-picolyl N′-oxide, N,N′-isopropylidene, N-salicylidene,N-(5,-dimethyl-3-oxo-1-cyclohexenyl), N-nitro, N-oxide,N-diphenylphosphinyl, N-dimetylthiophosphinyl, N-dimetylthiophosphinyl,N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,N-2,4,6-trimethylbenzenesulfonyl, N-toluenesulfonyl, N-benzylsulfonyl,N-trifluoromethylsulfonyl, and N-phenyacylsulfonyl. In one embodiment,the amino protective group is selected from the group consisting ofN-allyl, N-phenacyl, N-3-acetoxypropyl, quaternary ammonium salts,N-methyoxymethyl, N-benzyloxymethyl, N-pivaloyloxymethyl, andN-tetrahydropyranyl. In one embodiment, the amino protective group isN-tetrahydropyranyl.

If there is a discrepancy between a depicted structure and a name givento that structure, the depicted structure controls. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold, wedged, or dashed lines, thestructure or portion of the structure is to be interpreted asencompassing all stereo isomers of it.

The term “solvate” refers to a complex formed by the combining of acompound of any formula as disclosed herein, and a solvent.

The term “hydrate” refers to the complex formed by the combining of acompound of any formula disclosed herein, and water.

Any formula or structure given herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶C and ¹²⁵L. Various isotopically labeledcompounds of the present disclosure, for example those into whichradioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated. Suchisotopically labeled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

In certain embodiments, the isotopically labeled compound is a compoundof formula 6. In other embodiments, the isotopically labeled compound isa compound of formula 6, wherein X is a halogen and R⁶ is an aminoprotective group. In another embodiment, the isotopically labeledcompound is a compound of formula 6, wherein X is Cl and R⁶ is THF orTHP.

The disclosure also includes compounds of any formula disclosed herein,in which from 1 to “n” hydrogens attached to a carbon atom is/arereplaced by deuterium, in which n is the number of hydrogens in themolecule. Such compounds may exhibit increased resistance to metabolismand may thus be useful for increasing the half-life of a compound of anyformula described herein, for instance formula II or formula III, whenadministered to a mammal. See, for example, Foster, “Deuterium IsotopeEffects in Studies of Drag Metabolism”, Trends Pharmacal. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well knownin the art, for example by employing starting materials in which one ormore hydrogen atoms have been replaced by deuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosuremay have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An¹⁸F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this disclosure and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., ²H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in a compound of any formuladisclosed herein. Similarly, in certain embodiments, tritium (i.e., ³H)is also regarded as a substituent in a compound of any formula disclosedherein. In certain embodiments, ¹⁴C is regarded as a substituent in acompound of any formula disclosed herein.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Base addition salts can be prepared, from inorganic and organic bases.Salts derived from in organic bases include, by way of example only,sodium, potassium, lithium, ammonium, calcium and magnesium salts.Further salts derived from organic bases include, but are not limitedto, salts of primary, secondary and tertiary amines, such as alkylamines, dialkyl amines, trialkylamines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,disubstituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenyl amities,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroarylamines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group. In the general structure N(R^(x))(R^(y))(R^(z)),mono-substituted amines have 2 of the three substituents on nitrogen(R^(x), R^(y) and R^(z)) as hydrogen; di-substituted amines have 1 ofthe three substituents on nitrogen (R^(x), R^(y) and R^(z)) as hydrogen;and tri-substituted amines have none of the three substituents onnitrogen (R^(x), R^(y) and R^(z)) as hydrogen. R^(x), R^(y) and R^(z)may be selected from a variety of substituents such as hydrogen,optionally substituted alkyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocyclyl and the like. The abovementioned amines referto the compounds wherein either one, two or three substituents on thenitrogen are as listed in the name. For example, the term “cycloalkenylamine” refers to cycloalkenyl-NH₂, wherein “cycloalkenyl” is as definedherein. The term “diheteroarylamine” refers to NH(heteroaryl)₂, wherein“heteroaryl” is as defined herein and so on.

Acid addition salts may be prepare from inorganic and organic acids.Acid addition salts may be prepared from inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic, acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

In some embodiments, a salt is a “pharmaceutically acceptable salt”. Apharmaceutically acceptable salt of a given compound, for instance acompound of Formula I, II, or III, refers to salts that retain thebiological effectiveness and properties of a given compound, and whichare not biologically or otherwise undesirable. See: P. Heinrich Stahland Camille G. Wermuth (Eds.) Pharmaceutical Salts: Properties,Selection, and Use (international Union of Pure and Applied Chemistry),Wiley-VCH; 2^(nd) revise Edition (May 16, 2011). In certain embodiments,a pharmaceutically acceptable salt of a given compound, for instance acompound of any of Formula I, II, or III, or a compound of any offormula 1-21, refers to that a salt form which is generally regarded assafe and suitable for use without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio. Exemplary pharmaceutically acceptable salts include acid additionsalts formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; orformed with organic acids such as acetic acid, benzenesulfonic acid,benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid,fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleicacid, malonic acid, mandelic acid, methanesulfonic acid,2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid,stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid,trimethylacetic acid, and the like, and salts formed when an acidicproton present in the parent compound is replaced by either a metal ion,e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as diethanolamine,triethanolamine, N-methylglucamine and the like. Also included in thisdefinition are ammonium and substituted or quaternized ammonium salts.Representative non-limiting lists of pharmaceutically acceptable saltscan be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977),and Remington: The Science and Practice of Pharmacy, R. Hendrickson,ed., 21st edition, Lippincott, Williams Wilkins, Philadelphia, Pa.,(2005), at p. 732, Table 38-5, both of which are hereby incorporated byreference herein.

Compounds described herein may be presented in the form of chemicalstructures or names. The compounds shown below in Table A are namedusing ChemBioDraw Ultra 12.0 and it should be understood that othernames may be used to identify compounds of the same structure. Othercompounds or radicals may be named with common names, or systematic ornon-systematic names. The compounds may also be named using othernomenclature systems and symbols that are commonly recognized in the artof chemistry including, for example, Chemical Abstract Service (CAS) andInternational Union of Pure and Applied Chemistry (IUPAC). The namingand numbering of the compounds of the present disclosure is illustratedwith the compounds shown in Table A below.

TABLE A

(8) (S)-tert-butyl (1-(5-fluoro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)propyl)carbamate

(9) 2-amino-6-fluorobenzoic acid

(10) (S)-2-((tert-butoxycarbonyl)amino)butanoic acid,

(10a) (S)-2-((tert-butoxycarbonyl)amino)propanoic acid,

(11) (S)-tert-butyl (1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate

(12) (S)-2-(1-aminopropyl)-5-fluoro-3- phenylquinazolin-4(3H)-one

(14) 5-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- yl)amino)propyl)quinazolin-4(3H)-one

(15) (S)-tert-butyl (1-(6-fluoro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)ethyl)carbamate

(16) 2-amino-5-fluorobenzoic acid

(17) (S)-tert-butyl (1-(6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate

(18) (S)-2-(1-aminoethyl)-6-fluoro-3- phenylquinazolin-4(3H)-one

(19) 6-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- yl)amino)ethyl)quinazolin-4(3H)-one

(II) (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

(III) (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one

Processes

In some embodiments, the application discloses a process forsynthesizing a compound of formula 1:

or a salt thereof, comprising step a) combining a compound of formula 2:

or a salt thereof,

and a compound of formula 3:

wherein the compound of formula 1 or a salt thereof is synthesized,

wherein R¹ is halo;

R² is selected from the consisting of H, and optionally substitutedC₁-C₈ alkyl; and

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, an amino protective group and an optionally substitutedpurinyl group.

In some embodiments, the application discloses a process forsynthesizing a compound of formula 1:

comprising step a) combining a compound of formula 2:

and a compound of formula 3:

wherein the compound of formula I is synthesized,

wherein R¹ is halo;

R² is selected from the group consisting of H, and optionallysubstituted C₁-C₈ alkyl; and

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, an amino protective group and an optionally substitutedpurinyl group.

In some embodiments, R¹ is F or Cl. In some embodiments, R¹ is F. Insome embodiments, R² is selected from the group consisting of methyl,ethyl or propyl. In some embodiments, R² is ethyl. In some embodiments,R² is unsubstituted C₁-C₈ alkyl. In some embodiments, R² isunsubstituted. In some embodiments, R³ is H and R⁴ is an aminoprotective group. In some embodiments, R³ is H and R⁴ is a carbamate. Insome embodiments, R³ is H and R⁴ is an optionally substituted purinylgroup. In some embodiments, R¹ is F or Cl; R² is selected from the groupconsisting of methyl, ethyl or propyl; R³ is H and R⁴ is an aminoprotective group. In some embodiments, R¹ is F or Cl; R² is selectedfrom the group consisting of methyl, ethyl or propyl; R³ is H and R⁴ isan optionally substituted purinyl group. In some embodiments, the aminoprotective group is selected from the group consisting of t-butylcarbamate, tetrahydropyranyl, alkylsilyl, benzyl, an optionallysubstituted purinyl group, and alkoxymethyl. In other embodiments, theamino protective group is carbamate. In some embodiments, the aminoprotective group is t-butyl carbamate (BOC) or 9-fluoroenylmethylcarbamate (FMOC). In some embodiments, the amino protective group isBOC. In some embodiments, when R⁴ is purinyl, the purinyl group has 0,1, 2, 3, 4, or 5 substituents, each independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Insome embodiments, the purinyl group has 0, 1, 2, or 3 of the above listof substituents. In some embodiments, the purinyl group has 0, 1, 2, or3 substituents selected from the group consisting of methyl, ethyl,propyl, NH₂, and N(CH₃)₂. In some embodiments, the purinyl group is haswith 0, 1 or 2 substituents selected from the group consisting ofmethyl, ethyl, propyl, NH₂, and N(CH₃)₂. In some embodiments, thepurinyl group has 1 substituent selected from the group consisting ofmethyl, ethyl, propyl, NH₂, and N(CH₃)₂. In some embodiments, thepurinyl group is unsubstituted.

In some embodiments, step a) farther comprises a step of combining adehydrating agent. In some embodiments, step a) (i.e., combining acompound of formula 2 or a salt thereof and a compound of formula 3 or asalt thereof) is performed in the presence of a dehydrating agent.Non-limiting examples of the dehydrating agent include DPP(diphenylphosphite), TPP (triphenylphosphite), DCC(N,N-dicyclohexylcarbodiimide), EDC(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), and CDI(1,1′-carbonyldiimidazole). In some embodiments, the dehydrating agentis DPP (diphenylphosphite), TPP (triphenylphosphite), DCC(N,N′-dicyclohexylcarbodiimide), EDC(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), CDI(1,1′-carbonyldiimidazole), or a mixture thereof. In some embodiments,the dehydrating agent is DPP. In some embodiments, step a) furthercomprises combining DPP. In some embodiments, step a) is performed inthe presence of DPP.

In some embodiments, the dehydrating reagent is combined with a compoundof formula 2 and a compound of formula 3, wherein the amount of thedehydrating reagent is in at least 2, 2.5, 3, 3.5, or 4 molarequivalents with respect to a compound of formula 2. In one embodiment,at least 2 molar equivalents of the dehydrating reagent with respect tothe compound of formula 2 is combined with the compound of formula 2 anda compound of formula 3. In a another embodiment, at least 2 molarequivalents of the DPP (diphenylphosphite) with respect to the compoundof formula 2 is combined with the compound of formula 2 and a compoundof formula 3. In a yet another embodiment, at least 2 molar equivalentsof the DPP (diphenylphosphite) with respect to the compound of formula 9is combined with the compound of formula 9 and a compound of formula 10,In a further embodiment, at least 2 molar equivalents of the DPP(diphenylphosphite) with respect to the compound of formula 16 iscombined with the compound of formula 16 and a compound of formula 10a.

In some embodiments, step a) further comprises a step of combining abase. In some embodiments, step a) (i.e., combining a compound offormula 2 or a salt thereof and a compound of formula 3 or a saltthereof) is performed in the presence of a base. Non-limiting examplesof the base includes pyridine, 4-dimethylaminopyridine, triethylamine,isopropylethylamine, imidazole, DABCO, DBU, 2,6-lutidine, andN,N-diisopropylethylamine. In some embodiments, the base is pyridine,4-dimethylaminopyridine, triethylamine, isopropylethylamine, imidazole,DABCO, DBU, 2,6-lutidine, N,N-thisopropylethylamine, or a mixturethereof. In some embodiments, the base is pyridine.

In some embodiments, step a) further comprises a solvent selected fromthe group consisting of pyridine, toluene, tetrahydrofuran, acetonitrileand 2-MeTHF. In some embodiments, step a) further comprises a solventselected from the group consisting of pyridine, toluene,tetrahydrofuran, acetonitrile, 2-MeTHF, and a mixture thereof.

In some embodiments, step a) includes combining a compound of formula 2or a salt thereof and a compound of formula 3 or a salt thereof with adehydrating agent, a base, a solvent, or a mixture thereof. In someembodiments, step a) includes combining a compound of formula 2 or asalt thereof and a compound of formula 3 or a salt thereof with adehydrating agent. In some embodiments, step a) includes combining acompound of formula 2 or a salt thereof and a compound of formula 3 or asalt thereof with a dehydrating agent and a base. In some embodiments,step a) includes combining a compound of formula 2 or a salt thereof anda compound of formula 3 or a salt thereof with a dehydrating agent, abase, and a solvent.

In some embodiments, step a) is performed at a temperature between 0 and45 degrees Celsius, between 15 and 40 degrees Celsius, or between 20 and30 degrees Celsius. In some embodiments, step a) is performed at atemperature below 45 degrees Celsius.

In some embodiments, the process further comprises step b) combining thecompound of formula 1 or a salt thereof; and

a compound of formula 22:

wherein n is 0-5; and each R⁵ is independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

wherein a compound of formula 4:

or a salt thereof is synthesized.

In some embodiments, the process further comprises step b) combining thecompound of formula 1; and a compound of formula 22:

wherein n is 0-5; and each R⁵ is independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

wherein a compound of formula 4:

is synthesized.

In some embodiments, the compound of formula 22 is a substitutedaniline. In some embodiments n is 1-5, and in other embodiments, n is1-3. In some embodiments n is 0-3. In some embodiments n is 0, 1, or 2.In some embodiments n is 0. In some embodiments, each R⁵ isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, nitro, thiol, cyano, cycloalkyl,heterocyclyl, aryl, and heteroaryl. In some embodiments, each R⁵ isindependently C₁-C₄-alkyl or halo. In other embodiments, n is 1, 2, or3; and R⁵ is selected from a group consisting of alkyl and halo. In someembodiments, n is 1, 2, or 3; and each R⁵ is independently selected froma group consisting of C₁-C₄-alkyl or halo. In yet other embodiments, nis 1, 2, or 3; and R⁵ is selected from a group consisting of methyl, F,and Cl. In some embodiments, n is 1, 2, or 3; and each R⁵ isindependently selected from a group consisting of methyl, F, and Cl. Insome embodiments, the compound of formula 22 is 2,6-difluoroaniline.

In some embodiments, step b) is performed at a temperature between 0 anddegrees Celsius; between 20 and 70 degrees Celsius; between 40 and 60degrees Celsius; or between 45 and 55 degrees Celsius.

In some embodiments, the process further comprises step e) combining thecompound of formula 4 or a salt thereof, wherein at least one of R₃ andR₄ of the compound of formula 4 is an amino protective group; and

one or more reagents, wherein the one or more reagents are used toremove the amino protective group; wherein a compound of formula 5:

or a salt thereof is synthesized.

In some embodiments, the process further comprises step e) combining thecompound of formula 4, wherein at least one of R₃ and R₄ of the compoundof formula 4 is an amino protective group; and

one or more reagents, wherein the one or more reagents are used toremove the amino protective group; wherein a compound of formula 5:

or a salt thereof is synthesized.

In some embodiments, the process further comprises step c) combining thecompound of formula 4, wherein at least one of R₃ and R₄ of the compoundof formula 4 is an amino protective group; and

two or more reagents, wherein one of the one or more reagents is used toremove the amino protective group and wherein another of the one or morereagents is an acid; wherein a compound of formula 5:

or a salt thereof is synthesized.

In some embodiments, the acid is hydrochloric acid.

In some embodiments, the process further comprises step d) combining thecompound of formula 5 or a salt thereof and a compound of formula 6:

wherein X is selected from the group consisting of halogen, mesyl,mesylate, tosyl and tosylate; and

R⁶ is hydrogen or an amino protective group; wherein a compound offormula 7:

or a salt thereof is synthesized.

In some embodiments, the process further comprises step d) combining thecompound of formula 5 or a salt thereof and a compound of formula 6:

wherein X is selected from the group consisting of halogen, mesyl,mesylate, tosyl and tosylate; and

R⁶ is hydrogen or an amino protective group; herein a compound offormula 7:

is synthesized.

In some embodiments, the process further comprises step c) combining thecompound of formula 4 or a salt thereof, wherein at least one of R₃ andR₄ of the compound of formula 4 is an amino protective group; and

one or more reagents, wherein the one or more reagents are used toremove the amino protective group; wherein a compound of formula 5:

or a salt thereof is synthesized; and

step d) combining the compound of formula 5 or a salt thereof and acompound of formula 6:

wherein X is selected from the group consisting of halogen, mesyl,mesylate, tosyl and tosylate; and

R⁶ is hydrogen or an amino protective group; wherein a compound offormula 7:

or a salt thereof is synthesized.

In some embodiments, the process further comprises step e) combining thecompound of formula 4, wherein at least one of and R₄ of the compound offormula 4 is an amino protective group; and

one or more reagents, wherein the one or more reagents are used toremove the amino protective group; wherein a compound of formula 5:

or a salt thereof is synthesized; and

step d) combining the compound of formula 5 or a salt thereof and acompound of formula 6:

wherein X is selected from the group consisting of halogen, mesyl,mesylate, tosyl and tosylate; and

R⁶ is hydrogen or an amino protective group; wherein a compound offormula 7:

is synthesized.

In some embodiments, the compound of formula (5) is a salt. In someembodiments, the compound of formula (5) is an HCl salt.

In some embodiments, the compound of formula (7) is a salt. In someembodiments, the compound of formula (7) is an HCl salt.

In some embodiments, X is halogen. In other embodiments, X is Cl or Br.In other embodiments, X is Cl.

In some embodiments, step c) further comprises combining a solventselected from the group consisting of acetonitrile, methanol, ethanol,isopropanol, n-propanol THF, water, and toluene. In some embodiments,step c) is performed in the presence of a solvent selected from thegroup consisting of acetonitrile, methanol, ethanol, isopropanol,n-propanol THF, water, toluene and mixtures thereof.

In some embodiments, step c) comprises combining one or more reagentsfor the deprotection of amino protective groups. For instance, if theamino protective group is an alkoxymethyl or a carbamate, such as at-butyl carbamate or Fmoc, then the one or more reagents is an acid. Infurther embodiments, the acid is a mineral acid. Non-limiting examplesof mineral acids include hydrochloric acid (HCl), nitric acid (HNO₃),phosphoric acid (H₃PO₄), sulfuric acid (H₂SO₄), boric acid (H₃BO₃),hydrofluoric acid (HF), hydrobromic acid (HBr), and perchloric acid(HClO₄). In some embodiments, the reagent is hydrochloric acid (HCl),nitric acid (HNO₃), phosphoric acid (H₃PO₄), sulfuric acid (H₂SO₄),boric acid (H₃BO₃), hydrofluoric acid (HF), hydrobromic acid (HBr),perchloric acid (HClO₄), or a mixture thereof. In other embodiments, theacid is trifluoroacetic acid (TFA). In another example, if the aminoprotective group is an alkyl silyl group, the one or more reagents aretetra-n-butylammonium fluoride (TBAF) and/or trifluoroacetic acid (TFA).In yet another example, if the amino protective group is benzyl, thenthe one or more reagents are Pd/C and H₂.

In some embodiments, step c) is performed at a temperature between 0 and70 degrees Celsius; between 20 and 60 degrees Celsius; or between 35 and50 degrees Celsius.

In some embodiments, the compound of formula 5 is synthesized as thefree base, whereas in other embodiments, the compound of formula 5 issynthesized as a salt. In one embodiment, the compound of formula 5 isthe salt of the compound of formula 12. In another embodiment, thecompound of formula 12 is synthesized as the HCl salt. In yet otherembodiments, the compound of formula 12 is synthesized as free base. Inadditional embodiments, the compound of formula 5 is the free base ofthe compound of formula 18, In some other embodiments, the compound offormula 5 is the salt of the compound of formula 18. By way of example,preparation of the salt can be followed by a neutralization step tosynthesize the free base.

The choice of synthesizing either a salt or free base form may depend onthe materials physical properties. In one embodiment, for stabilityreasons and manufacturing reasons, such as ease of handling, thecompound of formula 12 is synthesized and/or isolated as the salt. Inanother example, the compound of formula 18 is synthesized and/orisolated as the free base, which is sufficiently stable and easy tohandle.

In some embodiments, the compound of formula 5 or a salt thereof iscrystallized from one or more solvents independently selected from thegroup comprising water, methanol, ethanol, isopropanol, n-propanol,concentrated NH₄OH, acetonitrile, (tert-butyl methyl ether), DCM(dichloromethane), EtOAc (ethyl acetate), iPrOAc (isopropylacetate),toluene, 2-Me-THF, DIPE (diisopropylether), heptane and heptanes. Insome embodiments, the compound of formula 5 or a salt thereof iscrystallized from one or more solvents selected from the groupconsisting of water, NH₄OH, acetonitrile, isopropanol, toluene, andmixtures thereof. In one embodiment, the one or more solvents are i)water, NH₄OH, and acetonitrile; or ii) isopropanol and toluene.

In some embodiments, step d) comprises a step of combining a baseselected from the group consisting of triethylamine, pyridine, Hunig'sbase, and a carbonate base. In some embodiments, step d) comprises astep of combining a base selected from the group consisting oftriethylamine, pyridine, Hunig's base, a carbonate base, andcombinations thereof.

In some embodiments, step d) further comprises combining a solventselected from the group consisting of water, an alcoholic solvent, andcombinations thereof.

In some embodiments, step d) includes combining the compound of formula5 or a salt thereof and a compound of formula 6 with a base or asolvent. In some embodiments, step d) includes combining the compound offormula 5 or a salt thereof and a compound of formula 6 with a base. Insome embodiments, step d) includes combining the compound of formula 5or a salt thereof and a compound of formula 6 with a solvent. In someembodiments, step d) includes combining the compound of formula 5 or asalt thereof and a compound of formula 6 with a base and a solvent.

In some embodiments, step d) is performed at a temperature between 35and 110 degrees Celsius; between 40 and 90 degrees Celsius; between 50and 80 degrees Celsius; or between 60 and 90 degrees Celsius.

In some embodiments, the compound of formula 7 or a salt thereof iscrystallized from one or more solvents selected from the groupconsisting of alcohol and water. In other embodiments, the one or moresolvents are methanol and water; ii) ethanol and water; iii) propanoland water; or iv) isopropanol and water.

In some embodiments, the compound of formula 6 is an unprotected purinylcompound, wherein R⁶ is hydrogen. In alternative embodiments, thecompound of formula 6 is a protected purinyl compound wherein R⁶ is anamino protecting group. Use of the protected purinyl compound, such asthe compound of formula 13, to synthesize a compound of formula 7 or asalt thereof has been observed to proceed faster, with less dipurineadducts, and at a higher yield compared to use of an unprotected purinylcompound.

In one embodiment, if R⁶ is an amino protective group, the processfurther comprises step e) combining the compound of formula 7, or a saltthereof, and

one or more reagents, wherein the one or more reagents are used toremove the amino protective group, wherein a compound of formula I:

or a salt thereof is synthesized. In one embodiment, R⁶ is an aminoprotective group.

In one embodiment, if R⁶ is an amino protective group, the processfurther comprises step e) combining the compound of formula 7, or a saltthereof, and

one or more reagents, wherein the one or more reagents are used toremove the amino protective group, wherein a compound of formula I:

is synthesized.

As noted above, in certain embodiments, step c) comprises combining oneor more reagents for the deprotection of amino protective groups. Forinstance, if the amino protective group is an alkoxymethyl or acarbamate, such as a t-butyl carbamate or Fmoc, then the one or morereagents is an acid. In further embodiments, the acid is a mineral acid.Non-limiting examples of mineral acids include hydrochloric acid (HCl),nitric acid (HNO₃), phosphoric acid (H₃PO₄), sulfuric acid (H₂SO₄),boric acid (H₃BO₃), hydrofluoric acid (HF), hydrobromic acid (HBr), andperchloric acid (HClO₄). In some embodiments, the reagent ishydrochloric acid (HCl), nitric acid (HNO₃), phosphoric acid (H₃PO₄),sulfuric acid (H₂SO₄), boric acid (H₃BO₃), hydrofluoric acid (HF),hydrobromic acid (HBr), perchloric acid (HClO₄), or a mixture thereof.In other embodiments, the acid is trifluoroacetic acid (TFA). In anotherexample, if the amino protective group is an alkyl silyl group, the oneor more reagents are tetra-n-butylammonium fluoride (TBAF) and/ortrifluoroacetic acid (TFA). In yet another example, if the aminoprotective group is benzyl, then the one or more reagents are Pd/C and

In yet further embodiments R⁶ is THP (tetrahydropyranyl). In someembodiments, R⁶ is THP and the one or more reagents used to remove theamino protective group is an acid. It has been discovered thatnon-aqueous acidic reaction conditions help avoid undesirable reactionssuch as degradation and formation of ring-opening side products. In someembodiments, the acid is generated in situ. In some embodiments, removalof the THP protective group proceeds to completion or near completion inthe absence of water. In one embodiment, removal of the THP protectivegroup proceeds to completion or near completion under anhydrousconditions. In another embodiment, removal of the THP protective groupproceeds to completion or near completion with less than 0.5% waterpresent. In a further embodiment, the acid is generated in situ. Forexample, ethanol and acetyl chloride may be used to generate HCl insitu. In some embodiments, step e) comprises an acid selected from thegroup consisting of a mineral acid, TFA and a Lewis acid. In someembodiments the acid is HCl. In another embodiment, R⁶ is methyl2-trimethylsilylethyl ether (SEM) and the one or more reagents used toremove the protective group is a fluoride ion.

Deprotection is considered near completion when at least 90%, 95%, 97%,98%, 99%, 99.% or 99.9% of the protected material is deprotected.

In some embodiments, step e) is performed at a temperature between 30and 70 degrees Celsius; between 40 and 60 degrees Celsius; or between 25and 50 degrees Celsius.

In some embodiments, the compound of formula I or a salt thereof iscrystallized from one or more solvents selected from the groupcomprising water, ethanol, methanol, isopropanol, n-propanol andacetone. In other embodiments, the one or more solvents are i) water;ii) ethanol; iii) acetone; iv) water and ethanol; or v) water, ethanoland acetone.

In some of the foregoing embodiments, the compound of formula 1 is

or a salt thereof.

In some of the foregoing embodiments, the compound of formula 1 is

or a pharmaceutically acceptable salt thereof.

In some of the foregoing embodiments, the compound of formula 1 is

In some of the foregoing embodiments, the compound of formula 2 is

In some of the foregoing embodiments, the compound of formula 3 is

In some of the foregoing embodiments, the compound of formula 4 is

or a salt thereof.

In some of the foregoing embodiments, the compound of formula 4 is

or a pharmaceutically acceptable salt thereof.

In some of the foregoing embodiments, the compound of formula 4 is

In some of the foregoing embodiments, the compound of formula 5 is

or a salt thereof.

In some of the foregoing embodiments, the compound of formula 5 is

or a pharmaceutically acceptable salt thereof.

In some of the foregoing embodiments, the compound of formula 5 is

In some of the foregoing embodiments, the compound of formula 6 is

In some of the foregoing embodiments, the compound of formula 7 is

or a salt thereof.

In some of the foregoing embodiments, the compound of formula 7 is

or a pharmaceutically acceptable salt thereof.

In some of the foregoing embodiments, the compound of formula 7 is

In some of the foregoing embodiments, the compound of formula I is

or a salt thereof.

In some of the foregoing embodiments, the compound of formula I is

or a pharmaceutically acceptable salt thereof.

In some of the foregoing embodiments, the compound of formula I is

The processes described herein provide an efficient synthesis. Inaddition, the processes reduce or minimize certain process steps and/orside products, such as racemization of chiral centers duringdeprotection conditions. Furthermore, the processes disclosed herein maybe suitable for various purposes, such as one or more of laboratory,industrial, commercial, non-commercial, manufacturing,non-manufacturing, regulatory, non-regulatory, medical, non-medical,pharmaceutical, and experimental uses.

By way of example, the processes of the present application may besuitable for making compounds of the formulas disclosed herein, in theamounts of ling, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1g, 5 g, 1.0 g, 50 g, 100 g, 250 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, 100kg, 250 kg, 500 kg, 750 kg, 1000 kg, 2500 kg, and 5000 kg, in a singlebatch. In addition, the processes of the present application may besuitable for making compounds in the amounts between 1-100 mg, 1-500 mg,1-1000 mg, 1-100 g, 1-500 g, 1-1000 g, 10-1000 kg, 500-1000 kg,1000-2000 kg, 1000-5000 kg, and more than 5000 kg in a single batch.Additionally, the processes of the present application may be suitablefor making compound in the amounts of at least 1 mg, 100 mg, 1 g, 10 g,100 g, 11 g, 10 kg, 1.00 kg, 1000 kg, 2500 kg, and 5000 kg, in a singlebatch. Also, the processes described herein may be used for makingcompounds in single or multiple batches, or incontinuous/semi-continuous processes. In some embodiments, the processis a batch process. In some embodiments, the process is a continuousprocess. In some other embodiments, the process is a semi-continuousprocess.

By way of example, the processes of the present application may utilizeat least about 1 mmol, 10 mmol, 100 mmol, 1 mol, 5 mol, 10 mol, 20 mol,50 mol, or 100 mol of at least one starting material. The startingmaterial includes any of the starting or intermediate compoundsdisclosed herein, a salt thereof, or a reagent.

Compounds

In some embodiments, the application discloses the compound of formula1:

or a salt thereof, wherein R¹ is selected from the group consisting ofhalo and optionally substituted C₁-C₈ alkyl; R² is selected from thegroup consisting of H and optionally substituted C₁-C₈ alkyl, and R³ andR⁴ are each independently selected from the group consisting, of anamino protective group and an optionally substituted purinyl group. Insome embodiments, R¹ is selected from the group consisting of halo andC₁-C₈ alkyl. In some embodiments, R¹ is halo. In some embodiments, R² isselected from the group consisting of H and C₁-C₈ alkyl. In someembodiments, R² is C₁-C₈ alkyl. In some embodiments, R² is C₁-C₄ alkyl.In some embodiments, R¹ is selected from the group consisting of haloand C₁-C₈ alkyl; R² is selected from the group consisting of H and C₁-C₈alkyl, and R³ and R⁴ are each independently selected from the groupconsisting of an amino protective group and an optionally substitutedpurinyl group. In some embodiments, R¹ is halo; R² is C₁-C₈ alkyl, andR³ and R⁴ are each independently selected from the group consisting ofan amino protective group and an optionally substituted purinyl group.In some embodiments, R¹ is halo; R² is C₁-C₄ alkyl, and R³ and R⁴ areeach independently selected from the group consisting of an aminoprotective group and an optionally substituted purinyl group. In furtherembodiments, R³ is an amino protective group and R⁴ is an optionallysubstituted purinyl group. In further embodiments, R³ and R⁴ are aminoprotective groups. In further embodiments, R³ is an amino protectivegroup and R⁴ is a purinyl group.

In some embodiments, the application discloses the compound of formula1:

or a salt thereof; and wherein the compound of formula 1 or a saltthereof is synthesized by a process comprising

step a) combining a compound of formula 2:

or a salt thereof,

and a compound of formula 3:

wherein the compound of formula 1 or a salt thereof is synthesized,

wherein R¹ is halo;

R² is selected from the group consisting of H, and optionallysubstituted C₁-C₈ alkyl; and R³ and R⁴ are each independently selectedfrom the group consisting of an amino protective group and an optionallysubstituted purinyl group. In other embodiments, R¹, R², R³ and R⁴ areas defined above for the compound of formula 1.

In some embodiments, the application discloses the compound of formula8:

or a salt thereof, wherein the compound of formula 8 or a salt thereofis synthesized by the process comprising combining a compound of formula9:

or a salt thereof,

and a compound of formula 10:

wherein the compound of formula 8 or a salt thereof is synthesized.

In some embodiments, the application discloses a compound of formula 14:

or a salt thereof, wherein the compound of formula 14 or a salt thereofis synthesized by a process comprising combining a compound of formula12:

or a salt thereof, and

a compound of formula 13:

wherein the compound of formula 14 is synthesized. In furtherembodiments, the process further comprises combining a compound offormula 11:

or a salt thereof, and

an acid, wherein the compound of formula 12 or a salt thereof issynthesized. In some embodiments, the process comprises combining acompound of formula 11:

and

an acid, wherein the compound of formula 12 or a salt thereof issynthesized. In yet further embodiments, the process further comprisescombining a compound of formula 8:

or a salt thereof, and

aniline, wherein the compound of formula 11 is synthesized. In yetanother embodiment, the process further comprises combining compound offormula 9:

or a salt thereof,

and a compound of formula 10:

wherein the compound of formula 8 or a salt thereof is synthesized.

In some embodiments, the application discloses a compound of formula 15:

or a salt thereof, wherein the compound of formula 15 or a salt thereofis synthesized by a process comprising combining a compound of formula16:

or a salt thereof,

and a compound of formula 10a:

wherein the compound of formula 15 or a salt thereof is synthesized.

In some embodiments, the application discloses a compound of formula15a:

or a salt thereof, wherein the compound of formula 15a or a salt thereofis synthesized by a process comprising combining a compound of formula16:

or a salt thereof,

wherein BB is halo, and a compound of formula 10a:

wherein AA is an amino protective group and wherein the compound offormula 15 or a salt thereof is synthesized. In some embodiments, BB isF. In some embodiments, the amino protective group is selected from thegroup consisting of t-butyl carbamate, tetrahydropyranyl, alkylsilyl,benzyl, an optionally substituted purinyl group, and alkoxymethyl. Inother embodiments, the amino protective group is carbamate. In someembodiments, the amino protective group is t-butyl carbamate (BOC) or9-fluoroenylmethyl carbamate (FMOC). In some embodiments, AA is t-butylcarbamate (BOC).

In some embodiments, the application discloses a compound of formula 19:

or a salt thereof, wherein the compound of formula 19 or a salt thereofis synthesized by a process comprising combining a compound of formula18:

or a salt thereof, and

a compound of formula 13:

wherein a compound of formula 19 or a salt thereof is synthesized. Infurther embodiments, the process further comprises combining a compoundof formula 17:

or a salt thereof, and

an acid, wherein the compound of formula 18 or a salt thereof issynthesized. In some embodiments, the process further comprisescombining a compound of formula 17:

and

an acid, wherein the compound of formula 18 or a salt thereof issynthesized. In yet further embodiments, the process further comprisescombining a compound of formula 15:

or a salt thereof, and

aniline, wherein the compound of formula 17 is synthesized. In yetanother embodiment, the process further comprises combining compound offormula 16:

or a salt thereof,

and a compound of formula 10:

wherein the compound of formula 15 or a salt thereof is synthesized.

In some embodiments, the application discloses a compound of formula 20:

or a salt thereof, wherein the compound of formula 20 or a salt thereofis synthesized by a process comprising combining a compound of formula9:

and

a compound of formula 10:

wherein the compound of formula 20 or a salt thereof is synthesized. Insome embodiments, the process further comprises synthesizing a compoundof formula 8:

or a salt thereof. In some embodiments, the compound of formula 8 or asalt thereof ring-opens to form the compound of formula 20 or a saltthereof. In some embodiments, the compound of formula 20 is anintermediate that is formed during the preparation of the compound offormula 8.

A compound of formula 21:

or a salt thereof, wherein the compound of formula 21 or a salt thereofis synthesized by a process comprising

combining a compound of formula 16:

or a salt thereof,

and a compound of formula 10a:

wherein the compound of formula 21 or a salt thereof is synthesized. Insome embodiments, the process further comprises synthesizing a compoundof formula 15:

or a salt thereof. In some embodiments, the compound of formula 15 or asalt thereof ring-opens to form the compound of formula 21 or a saltthereof. In some embodiments, the compound of formula 21 is anintermediate that is formed during the preparation of the compound offormula 15.

By way of example, the compositions of the present application maycomprise at least 2000 kg, 1000 kg, 750 kg, 500 kg, 250 kg, 100 kg, 10kg, 1 kg, 0.5 kg, 50 g, 5 g, or 5 g of a compound of a formula disclosedherein or a salt thereof. In some embodiments, compositions may comprisea multi-kilogram amount of a compound of a formula disclosed herein orsalt thereof. In other embodiments, compositions of the presentdisclosure may comprise at least about 1 mmol, 10 mmol, 100 mmol, 1 mol,5 mol, 10 mol, 20 mol, 50 mol, or 100 mol of a compound of a formuladisclosed herein or a salt thereof. In addition to a compound of aformula disclosed herein or a salt thereof, composition may furthercomprise solvents, reagents, or combinations thereof. In another aspect,compositions may consist essentially of a compound of a formuladisclosed herein or a salt thereof.

By way of example, the resulting compounds from the processes describedherein may be used in a pharmaceutical composition. In anotherembodiment, provided is a pharmaceutical composition comprising aresulting compound from the processes disclosed herein or a saltthereof, and one or more pharmaceutically acceptable carriers orexcipients.

EXAMPLES Example 1. Synthesis of a Compound of Formula 17

A compound of formula 16 (1.0 kg, 1.0 eq), a compound of formula 10 (1.5kg, 1.2 eq) and pyridine (3.0 kg) were added to reactor A. The mixturewas agitated at 19 to 25° C. and diphenylphosphite (6.1 kg, 4.0 eq) wasadded to the mixture over at least 2 h while maintaining the internaltemperature at less than about 35° C. The reaction mixture was adjustedto 19 to 25° C. and agitated until the reaction was deemed complete byHPLC analysis (1-3 h). Aniline (0.7 kg, 1.2 eq) was added over a minimumof 1 h while maintaining the internal temperature at less than about 40°C. The reaction mixture was then adjusted to 45 to 55° C. and agitateduntil the reaction is deemed complete. The reaction mixture was cooledto 19 to 25° C. and toluene (13 kg) was added followed by a prepared 1MHCl solution (10 kg) while maintaining the internal temperature, at lessthan about 30° C. The biphasic mixture was agitated at about 22° C. forat least 30 minutes and then allowed to settle. The aqueous layer wasseparated and discarded. A second portion of 1M HCl (10 kg) was added tothe organic layer in reactor A. The biphasic mixture was agitated at 19to 25° C. for at least 30 minutes and then allowed to settle. Theaqueous layer was separated and discarded. A compound of formula 17 wascarried forward to the next step as a stock solution in toluene.

Example 2. Synthesis of a Compound of Formula 18

To the stock solution of a compound of formula 17 in toluene was addedacetonitrile (8.4 kg) and concentrated HCl (2.2 kg) while maintainingthe internal temperature at no more than 30° C.

The reaction mixture was adjusted to 19 to 25° C. and agitated until thereaction was deemed complete. Water (5 kg) was added and the biphasicmixture was agitated at 19 to 25° C. for at least 30 minutes and thenallowed to settle. The bottom aqueous layer was separated andtransferred to reactor B (product was in the aqueous layer). Water (10kg) was then added to the organic layer in reactor A. The biphasicmixture was agitated at 19 to 25° C. for at least 30 minutes and thenallowed to settle. The bottom aqueous layer was separated andtransferred to reactor B (combining with the first aqueous phase).Toluene (4 kg) was added to the combined aqueous layers in reactor B andthe biphasic mixture was agitated at 19 to 25° C. for at least 30minutes and then allowed to settle. The bottom aqueous layer wasseparated and transferred to reactor A. Toluene (4 kg) was added toreactor A and the biphasic mixture was agitated at 19 to 25° C. for atleast 30 minutes and then allowed to settle. The bottom aqueous layerwas separated and transferred to reactor B. The aqueous phase was thenpartially concentrated under vacuum to 18 to remove toluene and reduceacetonitrile levels to no more than 3.5%. The aqueous phase was thentransferred, in portions, to reactor B containing water (5 kg), ammoniumhydroxide (6.5 kg, 8.0 eq) and acetonitrile (0.8 kg) while maintainingthe internal temperature at no more than 19 to 25° C. The resultingslurry was agitated at 19 to 25° C. for ca 1 h before filtering. Thefilter cake was rinsed with water (3 kg) and then dried under vacuum atno more than 50° C. to afford 18. ¹H NMR (400 MHz, CDCl₃): δ 7.82 (dd,J=8.4, 2.2 Hz, 1H), 7.71 (dd, J=9.2, 5.0 Hz, 1H), 7.55-7.45 (m, 4H),7.27 (d, J=6.4 Hz, 2H), 3.69 (q, 6.4 Hz, 1H), 2.01 (s, 2H), 1.27 (d,J=6.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 162.3, 161.9, 160.5, 159.8,144.4, 136.6, 130.3, 130.2, 129.9, 129.0, 128.9, 128.4, 123.4, 123.2,1.22.3, 122.2, 112.1, 111.9, 48.7, 23.7 (signal splitting due tofluorine results in additional peaks).

Example 3. Synthesis of a Compound of Formula 19

A compound of formula 18 (1.0 kg, a compound of formula 13 (0.9 kg, 1.1eq), triethylamine (0.5 kg, 1.5 eq), water (4 kg) and EtOH (2 kg) wereadded to reactor A. The mixture was adjusted to 75 to 85° C. andagitated until the reaction was deemed complete. The mixture was thenadjusted to 19 to 25° C. and agitated for ca 1 h before filtering. Theisolated compound of formula 19 solid was rinsed with water (2 kg) andheptanes (2×3 kg) and then dried under vacuum. ¹H NMR (400 MHz, CDCl₃):δ 8.28 (d, J=2 Hz, 1H), 8.00 (bs, 1H), 7.89 (dd, J=8.8, 3.0 Hz, 1H),7.73 (m, 1H), 7.59 (m, 3H), 7.48 (m, 2H), 7.35 (m, 1H), 6.68 (m, 1H),5.69 (dd, J=10.0, 3.0 Hz, 1H), 5.24 (bs, 1H), 4.1.6 (dd, J=11.6, 2.0 Hz,1H), 3.77 (tt, J=11.2, 1.4 Hz, 1H), 2.06 (m, 3H), 1.75 (m, 3H), 1.47 (d,J=6.8 Hz, 3H).

Example 4. Synthesis of a Compound of Formula III

To reactor A was added a compound of formula 19 followed by EtOH (4.2kg). Acetyl chloride (0.33 kg, 1.2 eq) was then added slowly whilemaintaining the internal temperature at less than about 40° C. Themixture was then adjusted to 19 to 25° C. and agitated until thereaction was deemed complete. After adjusting the temperature to 5 to15° C., 0.84 kg of a prepared 4.5% sodium carbonate solution was addedto the reaction mixture followed by water (1 kg) while maintaining theinternal temperature at 5 to 15° C. To reactor B was added 5.44 kg of aprepared 4.5% sodium carbonate solution and the contents were warmed to65 to 75° C. Approximately 20% of the solution held in reactor A wasthen transferred to the aqueous solution in reactor B while keeping theinternal temperature at 65 to 75° C. The mixture was aged for about 30minutes until a slurry was formed. The remaining solution from reactor.A was transferred to reactor B over a period of about 1 h whilemaintaining the internal temperature at 65 to 75° C. The slurry wasagitated at 65 to 75° C. for 1 to 5 h until a thick slurry was formed.The contents were then adjusted to 1.9 to 25° C. over about 1 h andagitated about 1 h before filtering. The wet cake was rinsed with water(10 kg) and then dried under vacuum at about 65° C. ¹H NMR (400 MHz,CDCl₃): δ 8.33 (s, 1H), 7.98 (br, 1H), 7.90 (dd, J=8.4, 2.8 Hz, 1H),7.74 (dd, J=8.8, 5.2 Hz, 1H), 7.65-7.57 (m, 3H), 7.51-7.45 (m, 2H), 7.37(m, 1H), 6.84 (bd, J=8.8 Hz, 1H), 5.27 (br, 1H), 1.75 (br, 1H), 1.50 (d,J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CDCl₃): δ −111.11 (referenced to TFA at−76.5 ppm).

The invention claimed is:
 1. A process for synthesizing a compound offormula (II):

or a salt thereof, comprising combining a compound of formula (14):

or a salt thereof, and one or more reagents to remove the aminoprotective group tetrahydropyranyl (THP) from the compound of formula(14), wherein the one or more reagents comprise an acid, and wherein thecompound of formula (14), or a salt thereof, and the one or morereagents are combined under conditions having less than 0.5% waterpresent.
 2. The process of claim 1, further comprising combining acompound of formula (12):

or a salt thereof, and a compound of formula (13):

to provide the compound of formula (14), or a salt thereof.
 3. Theprocess of claim 2, further comprising combining a compound of formula(11):

or a salt thereof, and one or more reagents to remove the aminoprotective group t-butyl carbamate (BOC) from the compound of formula(11), or a salt thereof, to provide the compound of formula (12), or asalt thereof, wherein the one or more reagents comprise an acid.
 4. Theprocess of claim 2, wherein the compound of formula (14), or a saltthereof, is crystallized from one or more solvents selected from thegroup consisting of alcohol, water, and combinations thereof.
 5. Theprocess of claim 3, wherein the one or more reagents combined with thecompound of formula (11), or a salt thereof, comprises a mineral acid ortrifluoroacetic acid (TFA).
 6. The process of claim 5, wherein themineral acid is hydrochloric acid.
 7. The process of claim 3, comprisingcombining the compound of formula (11), or a salt thereof, and the oneor more reagents in the presence of a solvent selected from the groupconsisting of acetonitrile, methanol, ethanol, isopropanol, n-propanol,tetrahydrofuran (THF), water, toluene and mixtures thereof.
 8. Theprocess of claim 3, comprising combining the compound of formula (11),or a salt thereof, and the one or more reagents at a temperature between0 and 70 degrees Celsius.
 9. The process of any one of claim 3, whereinthe compound of formula (12), or a salt thereof, is crystallized fromone or more solvents selected from the group comprising water, methanol,ethanol, isopropanol, n-propanol, concentrated NH₄OH, acetonitrile,MTBE, DCM, EtOAc, iPrOAc, toluene, 2-Me-THF, DIPE (diisopropylether),heptane and heptanes.
 10. The process of claim 9, wherein the one ormore solvents are i) water, concentrated NH₄OH, and acetonitrile; or ii)isopropanol and toluene.
 11. The process of claim 2, further comprisingcombining the compound of formula (12), or a salt thereof, and thecompound of formula (13) with a base selected from the group consistingof triethylamine, pyridine, Hunig's base, and a carbonate base.
 12. Theprocess of claim 11, wherein the base is triethylamine.
 13. The processof claim 2, wherein the compound of formula (12), or a salt thereof, andthe compound of formula (13) are combined in the presence of a solventselected from the group consisting of water, an alcoholic solvent, andcombinations thereof.
 14. The process of claim 2, wherein the compoundof formula (12), or a salt thereof, and the compound of formula (13) arecombined at a temperature between 35 and 110 degrees Celsius.
 15. Theprocess of claim 1, wherein the one or more reagents combined with thecompound of formula (14), or a salt thereof, are selected from the groupconsisting of a mineral acid, TFA and a Lewis acid.
 16. The process ofclaim 15, wherein mineral acid is hydrochloric acid.
 17. The process ofclaim 1, wherein the compound of formula (14), or a salt thereof, andthe one or more reagents are combined under non-aqueous acidic reactionconditions.
 18. The process of claim 1, wherein the compound of formula(14), or a salt thereof, and the one or more reagents are combined underanhydrous conditions.
 19. The process of claim 1, wherein the process isperformed at a temperature between 30 and 70 degrees Celsius.
 20. Theprocess of claim 1, wherein the compound of formula (II), or a saltthereof, is crystallized from one or more solvents selected from thegroup comprising water, ethanol, methanol, isopropanol, n-propanol, andacetone.
 21. The process of claim 20, wherein the one or more solventsare i) water and ethanol; or ii) acetone.
 22. The process of claim 2,wherein the compound of formula (14), or a salt thereof, is crystallizedfrom one or more solvents selected from the group consisting ofisopropanol, n-propanol, ethanol, methanol, and water.
 23. The processof claim 1, wherein the process is operated in a batch process.
 24. Theprocess of claim 1, wherein at least 90% of the compound of formula(14), or a salt thereof, is deprotected to provide the compound offormula (II), or a salt thereof.